1. Field of the Invention
The present invention relates to a stabilized oral pharmaceutical formulation of prostaglandin E group (hereinafter, it is referred to as PGE group) and a process of preparing the formulation. More particularly, the invention relates to a stabilized oral PGE group formulation prepared from the lyophilized composition of an aqueous solution containing PGE group and at least a member selected from the group consisting of a thiol compound, dextrin, dextran, a lower alkyl cellulose, and a water-soluble salt of deoxycholic acid and a process of preparing the formulation.
2. Description of the Prior Art
PGE is the compound shown by the following formula ##STR1##
The compounds having the above-described basic structure include as PGE.sub.1, PGE.sub.2, PGE.sub.3, etc., and they are named according to the number of the double bonds in the structure. For example, PGE.sub.2 has two double bonds at the 5-position and 13-position of the structure. The PGE group in this invention includes the compounds having substituents such as the methyl group, methoxy group hydroxy group, oxo group, etc., at various positions of the structure. Typical examples of the PGE.sub.2 group are, for example, 16-methyl-PGE.sub.2, 3-methyl-PGE.sub.2, 3,16(R)-dimethyl-PGE.sub.2, 17-oxo-15-epi-PGE.sub.2, 16(R)-hydroxy-PGE.sub.2, 16,16-dimethyl-PGE.sub.2 -methyl ester, 4(R),16(R)-dimethyl-PGE.sub.2, 4(R),16(S)-dimethyl-PGE.sub.2, 4(S),16(R)-dimethyl-PGE.sub.2, 4(S),16(S)-dimethyl-PGE.sub.2, 16(R,S)-methyl-20-methoxy-PGE.sub.2, 16(R)-methyl-20-methoxy-PGE.sub.2, and 16(S)-methyl-20-methoxy-PGE.sub.2.
The PGE group exhibits, even at a small dose, wide pharmaceutical effects such as control of the contractive force of the uterus or of hypotensitive activity, the treatment and prophylaxis of digestive organ ulcers, the control of lipid metabolism, bronchodilator activity, etc., but has a fault in that the aqueous solution thereof is unstable (see, Brummer, "J. Pharm. Pharmacol.", 23, 804-805(1971) and Karmin et al; "European J. Pharmacol.", 4, 416-420(1968).
For preparing stable compositions of PGE.sub.2, there are known, for example, a method of preparing a concentrated stock solution of PGE.sub.2 by dissolving it in absolute alcohol as disclosed in U.S. Pat. No. 3,749,800 and a method of preparing a solution of PGE.sub.2 by dissolving it in an anhydrous aprotic dipolar organic solvent such as N,N-dimethylacetamide as disclosed in Belgian Pat. No. 790,840. When the compositions of PGE.sub.2 prepared by these methods are used as injections, they are usually diluted with water.
There is also known a method of stabilizing the PGE group by adding thereto an alkali metal sulfite salt as disclosed in U.S. Pat. No. 3,851,052 but the case of showing practically the stabilization effect by the method is limited to a stock solution of PGE prepared by dissolving it in alcohol together with an alkali metal sulfite salt and even in this case, however the potency of the solution about the stability becomes only about 70% when the solution is stored for 13 days at 60.degree. C.
Moreover, there is known a method of preparing a solid dispersion of prostaglandin in polyvinyl pyrrolidone as disclosed in U.S. Pat. No. 3,826,823. According to said method, 1 part of prostaglandin is dissolved in a suitable solvent together with 10-100 parts of polyvinyl pyrrolidone and then the solution is dried by, for example, lyophilization to disperse the prostaglandin in polyvinyl pyrrolidone. However, the method is accompanied by the disadvantage in that a small amount of water in the solution does not evaporate completely by lyophilization due to the high hygroscopicity of the polyvinyl pyrrolidone itself and also the lyophilized product obtained is liable to be decomposed by the remaining water. Therefore, the lyophilization procedure must be conducted for a long period of time. Still further, in the case of preparing formulations such as, for example, tablets using the lyophilized composition thus obtained, the composition becomes sticky by absorbing ambient moisture. This will clearly cause difficulties in preparing the composition. Further, the moisture way also causes the possibility of the decomposition of PEG group. These difficulties had not yet been solved.